title: Belinostat and panobinostat (HDACI): in vitro and in vivo studies in thyroid cancer.
abstract: OBJECTIVE
  Advanced thyroid cancer responds poorly to most therapies. New therapies and combinations are needed. The aim of this study was to examine both in vitro and in vivo activity of two relatively new histone deacetylase inhibitors (HDACIs), belinostat and panobinostat, and a variety of tyrosine kinase inhibitors (TKIs) against a panel of nine human thyroid cancer cell lines.
  
  
  METHODS
  The anti-proliferative activity and the effects of HDACIs, TKIs and their combinations on thyroid cancer cells were determined by cytotoxicity assays, microarray and immunoblot analyses. Synergism between HDACIs and TKIs was assessed by the median effects model of Chou-Talalay (Calcusyn(®)).
  
  
  RESULTS
  Belinostat and panobinostat were active against the thyroid cancer cell lines irrespective of their mutational composition, and belinostat was effective in preventing growth of human thyroid cancer xenografts in immunodeficient mice. Further studies showed that both HDACIs induced apoptosis. HDACI also elevated acetylated histone 3, p21(Waf), and PARP, and decreased levels of phosphorylated ERK and AKT (Ser473). RNA assay analysis suggested both HDACIs modulated genes associated with the cell cycle, DNA damage and apoptosis. Most of the TKI (pazopanib, motesanib, sorafenib and dasatinib) were either inactive in vitro or were active only at high doses. However, the novel combinations of either pazopanib or dasatinib TKIs with either belinostat or panobinostat synergistically inhibited cell growth of thyroid cancer cells in vitro.
  
  
  CONCLUSIONS
  In summary, these HDACIs either alone or combined with selected TKIs may have a role in treatment of aggressive thyroid cancer.
authors.affiliation: National University Hospital, National University Cancer Institute Singapore, 1E Kent Ridge Road, Singapore, 119228, Singapore.
authors.forename: Daniel
authors.initials: D
authors.lastname: Chan
authors.forename: Yun
authors.initials: Y
authors.lastname: Zheng
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Tyner
authors.forename: Wee Joo
authors.initials: WJ
authors.lastname: Chng
authors.forename: Wen Wen
authors.initials: WW
authors.lastname: Chien
authors.forename: Sigal
authors.initials: S
authors.lastname: Gery
authors.forename: Geraldine
authors.initials: G
authors.lastname: Leong
authors.forename: Glenn D
authors.initials: GD
authors.lastname: Braunstein
authors.forename: H Phillip
authors.initials: HP
authors.lastname: Koeffler
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D000077767:Panobinostat; D013449:Sulfonamides / Q000494:pharmacology*; D013964:Thyroid Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007211:Indoles; D013449:Sulfonamides; D000077767:Panobinostat; C487081:belinostat